Rituximab or cyclosporine in the treatment of membranous nephropathy

Fernando C. Fervenza, Gerald B. Appel, Sean J. Barbour, Brad H. Rovin, Richard A. Lafayette, Nabeel Aslam, Jonathan A. Jefferson, Patrick E. Gipson, Dana V. Rizk, John R. Sedor, James F. Simon, Ellen T. Mccarthy, Paul Brenchley, Sanjeev Sethi, Carmen Avila-casado, Heather Beanlands, John C. Lieske, David Philibert, Tingting Li, Lesley F. ThomasDolly F. Green, Luis A. Juncos, Lada Beara-lasic, Samuel S. Blumenthal, Amy N. Sussman, Stephen B. Erickson, Michelle Hladunewich, Pietro A. Canetta, Lee A. Hebert, Nelson Leung, Jay Radhakrishnan, Heather N. Reich, Samir V. Parikh, Debbie S. Gipson, Dominic K. Lee, Bruno R. Da Costa, Peter Jüni, Daniel C. Cattran

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

BACKGROUND B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensinsystem blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI],-9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.)

Original languageEnglish (US)
Pages (from-to)36-46
Number of pages11
JournalNew England Journal of Medicine
Volume381
Issue number1
DOIs
StatePublished - Jul 4 2019

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Membranous Glomerulonephritis
Cyclosporine
Proteinuria
Phospholipase A2 Receptors
Therapeutics
B-Lymphocytes
Confidence Intervals
Rituximab
Body Surface Area
Random Allocation
Autoantibodies
Creatinine
Body Weight
Safety
Antibodies

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fervenza, F. C., Appel, G. B., Barbour, S. J., Rovin, B. H., Lafayette, R. A., Aslam, N., ... Cattran, D. C. (2019). Rituximab or cyclosporine in the treatment of membranous nephropathy. New England Journal of Medicine, 381(1), 36-46. https://doi.org/10.1056/NEJMoa1814427

Rituximab or cyclosporine in the treatment of membranous nephropathy. / Fervenza, Fernando C.; Appel, Gerald B.; Barbour, Sean J.; Rovin, Brad H.; Lafayette, Richard A.; Aslam, Nabeel; Jefferson, Jonathan A.; Gipson, Patrick E.; Rizk, Dana V.; Sedor, John R.; Simon, James F.; Mccarthy, Ellen T.; Brenchley, Paul; Sethi, Sanjeev; Avila-casado, Carmen; Beanlands, Heather; Lieske, John C.; Philibert, David; Li, Tingting; Thomas, Lesley F.; Green, Dolly F.; Juncos, Luis A.; Beara-lasic, Lada; Blumenthal, Samuel S.; Sussman, Amy N.; Erickson, Stephen B.; Hladunewich, Michelle; Canetta, Pietro A.; Hebert, Lee A.; Leung, Nelson; Radhakrishnan, Jay; Reich, Heather N.; Parikh, Samir V.; Gipson, Debbie S.; Lee, Dominic K.; Da Costa, Bruno R.; Jüni, Peter; Cattran, Daniel C.

In: New England Journal of Medicine, Vol. 381, No. 1, 04.07.2019, p. 36-46.

Research output: Contribution to journalArticle

Fervenza, FC, Appel, GB, Barbour, SJ, Rovin, BH, Lafayette, RA, Aslam, N, Jefferson, JA, Gipson, PE, Rizk, DV, Sedor, JR, Simon, JF, Mccarthy, ET, Brenchley, P, Sethi, S, Avila-casado, C, Beanlands, H, Lieske, JC, Philibert, D, Li, T, Thomas, LF, Green, DF, Juncos, LA, Beara-lasic, L, Blumenthal, SS, Sussman, AN, Erickson, SB, Hladunewich, M, Canetta, PA, Hebert, LA, Leung, N, Radhakrishnan, J, Reich, HN, Parikh, SV, Gipson, DS, Lee, DK, Da Costa, BR, Jüni, P & Cattran, DC 2019, 'Rituximab or cyclosporine in the treatment of membranous nephropathy', New England Journal of Medicine, vol. 381, no. 1, pp. 36-46. https://doi.org/10.1056/NEJMoa1814427
Fervenza, Fernando C. ; Appel, Gerald B. ; Barbour, Sean J. ; Rovin, Brad H. ; Lafayette, Richard A. ; Aslam, Nabeel ; Jefferson, Jonathan A. ; Gipson, Patrick E. ; Rizk, Dana V. ; Sedor, John R. ; Simon, James F. ; Mccarthy, Ellen T. ; Brenchley, Paul ; Sethi, Sanjeev ; Avila-casado, Carmen ; Beanlands, Heather ; Lieske, John C. ; Philibert, David ; Li, Tingting ; Thomas, Lesley F. ; Green, Dolly F. ; Juncos, Luis A. ; Beara-lasic, Lada ; Blumenthal, Samuel S. ; Sussman, Amy N. ; Erickson, Stephen B. ; Hladunewich, Michelle ; Canetta, Pietro A. ; Hebert, Lee A. ; Leung, Nelson ; Radhakrishnan, Jay ; Reich, Heather N. ; Parikh, Samir V. ; Gipson, Debbie S. ; Lee, Dominic K. ; Da Costa, Bruno R. ; Jüni, Peter ; Cattran, Daniel C. / Rituximab or cyclosporine in the treatment of membranous nephropathy. In: New England Journal of Medicine. 2019 ; Vol. 381, No. 1. pp. 36-46.
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abstract = "BACKGROUND B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensinsystem blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60{\%}) in the rituximab group and 34 of 65 (52{\%}) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95{\%} confidence interval [CI],-9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60{\%}) in the rituximab group and 13 (20{\%}) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95{\%} CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17{\%}) in the rituximab group and in 20 (31{\%}) in the cyclosporine group (P = 0.06). CONCLUSIONS Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.)",
author = "Fervenza, {Fernando C.} and Appel, {Gerald B.} and Barbour, {Sean J.} and Rovin, {Brad H.} and Lafayette, {Richard A.} and Nabeel Aslam and Jefferson, {Jonathan A.} and Gipson, {Patrick E.} and Rizk, {Dana V.} and Sedor, {John R.} and Simon, {James F.} and Mccarthy, {Ellen T.} and Paul Brenchley and Sanjeev Sethi and Carmen Avila-casado and Heather Beanlands and Lieske, {John C.} and David Philibert and Tingting Li and Thomas, {Lesley F.} and Green, {Dolly F.} and Juncos, {Luis A.} and Lada Beara-lasic and Blumenthal, {Samuel S.} and Sussman, {Amy N.} and Erickson, {Stephen B.} and Michelle Hladunewich and Canetta, {Pietro A.} and Hebert, {Lee A.} and Nelson Leung and Jay Radhakrishnan and Reich, {Heather N.} and Parikh, {Samir V.} and Gipson, {Debbie S.} and Lee, {Dominic K.} and {Da Costa}, {Bruno R.} and Peter J{\"u}ni and Cattran, {Daniel C.}",
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TY - JOUR

T1 - Rituximab or cyclosporine in the treatment of membranous nephropathy

AU - Fervenza, Fernando C.

AU - Appel, Gerald B.

AU - Barbour, Sean J.

AU - Rovin, Brad H.

AU - Lafayette, Richard A.

AU - Aslam, Nabeel

AU - Jefferson, Jonathan A.

AU - Gipson, Patrick E.

AU - Rizk, Dana V.

AU - Sedor, John R.

AU - Simon, James F.

AU - Mccarthy, Ellen T.

AU - Brenchley, Paul

AU - Sethi, Sanjeev

AU - Avila-casado, Carmen

AU - Beanlands, Heather

AU - Lieske, John C.

AU - Philibert, David

AU - Li, Tingting

AU - Thomas, Lesley F.

AU - Green, Dolly F.

AU - Juncos, Luis A.

AU - Beara-lasic, Lada

AU - Blumenthal, Samuel S.

AU - Sussman, Amy N.

AU - Erickson, Stephen B.

AU - Hladunewich, Michelle

AU - Canetta, Pietro A.

AU - Hebert, Lee A.

AU - Leung, Nelson

AU - Radhakrishnan, Jay

AU - Reich, Heather N.

AU - Parikh, Samir V.

AU - Gipson, Debbie S.

AU - Lee, Dominic K.

AU - Da Costa, Bruno R.

AU - Jüni, Peter

AU - Cattran, Daniel C.

PY - 2019/7/4

Y1 - 2019/7/4

N2 - BACKGROUND B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensinsystem blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI],-9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.)

AB - BACKGROUND B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensinsystem blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI],-9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.)

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